WZ4003, a specific NUAK1 and NUAK2 inhibitor (A) Chemical structure of the NUAK1/NUAK2 inhibitor WZ4003. WZ4003, a specific NUAK1 and NUAK2 inhibitor (A)

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Presentation transcript:

WZ4003, a specific NUAK1 and NUAK2 inhibitor (A) Chemical structure of the NUAK1/NUAK2 inhibitor WZ4003. WZ4003, a specific NUAK1 and NUAK2 inhibitor (A) Chemical structure of the NUAK1/NUAK2 inhibitor WZ4003. (B) Wild-type (WT) GST–NUAK1 and GST–NUAK2 were assayed using 200 μM Sakamototide in the presence of 100 μM [γ-32P]ATP (~500 c.p.m./pmol) with the indicated concentrations of WZ4003. The IC50 graph was plotted using GraphPad Prism software with non-linear regression analysis. The results are presented as the percentage of kinase activity relative to the DMSO-treated control. Results are means±S.D. for triplicate reactions with similar results obtained in at least one other experiment. (C) Kinase profiling of the WZ4003 inhibitor at 1 μM was carried out against the panel of 140 kinases at the The International Centre for Protein Kinase Profiling (http://www.kinase-screen.mrc.ac.uk/). AMPK family kinases are indicated with an asterisk, LKB1 with a filled hexagon and NUAK1 with an arrow. The full names of the kinases can be found in the legend to Supplementary Table S1 (at http://www.biochemj.org/bj/457/bj4570215add.htm). (D) Wild-type (WT) GST–NUAK1 and GST–NUAK1[A195T] were purified from HEK-293 cells following transient transfection and relative levels of wild-type and mutant enzymes were analysed by Coomassie Blue staining of a polyacrylamide gel (bottom panel). Intrinsic kinase activities of the equivalent amounts of NUAK1 and NUAK1[A195T] were compared by carrying out a quantitative kinase activity assay by calculating the relative kinase-mediated incorporation of [γ-32P]ATP into the Sakamototide substrate peptide. Values are means±S.D. for an experiment carried out in triplicate. (E) As in (B) except that WZ4003 comparative IC50 values were derived for wild-type (WT) GST–NUAK1 and GST—NUAK1[A195T]. Sourav Banerjee et al. Biochem. J. 2014;457:215-225 ©2014 by Portland Press Ltd